This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are using a rhesus macaque model to develop vaccine strategies against HIV subtype C (also called clade C), the world's most prevalent subtype. For testing the efficacy of potential vaccines against HIV clade C, we developed hybrid viruses, called SHIVs, by combining genetic components of a monkey AIDS virus with a segment of HIV called envelope;we have developed three such viruses using envelopes from HIV clade C strains isolated from infected African infants. Our approach to develop a vaccine has been to generate: 1) immune cell-based responses to multiple viral components, and 2) neutralizing antibody-based immunity to envelope. Each HIV strain has a unique envelope, and to more closely mimic reality where vaccinated individuals will not be exposed to HIV strains identical to those used to prepare the vaccine components, we deliberately challenged our vaccinated monkeys with SHIVs in which the envelopes are mismatched compared to the envelope used for vaccination. In our study, monkeys that were immunized as infants against three different structural components of SHIV showed protection against both low-dose and high-dose challenges with two forms of a clade C SHIV, including one case of complete protection. We are now testing this vaccine strategy against multiple low-dose mucosal SHIV challenges. We are also following a set of animals, previously vaccinated and/or exposed to clade C SHIVs that have maintained high levels of envelope-specific antibodies that can neutralize many diverse strains of HIV. We are analyzing the fine-specificity of the antibody responses in these animals in order to identify specific sites of envelope recognized by neutralizing antibodies that are common among different HIV strains. This information will be important for the design of vaccine components to raise antibodies that would neutralize a broad range of HIV strains in vaccinated humans.